1. Field of the Invention
The invention relates to a process for preparing xcex1-haloketones.
2. Background Art
The preparation of xcex1-chloroketones by reacting an N-protected amino acid with alkyl chloroformates to give the mixed anhydride, reacting the mixed anhydride with diazomethane to give the diazoketone, and subsequently reacting the diazoketone with HCl to give the chloroketone is disclosed, for example, by S. W. Kaldor et al., J. Med. Chem. 1997, 40, 3979-3985. The process employs diazomethane, an explosive and carcinogenic gas which can only be used on the industrial scale at high risk. The preparation of xcex1-chloroketones by reacting an N-protected amino ester with a CH2Cl anion at low temperatures is disclosed, for example, by P. Chen et al., TETRAHEDRON LETT. 1997, 38(18), 3175-3178, and by U.S. Pat. Nos. 5,481,011; 5,523,463; U.S. Pat. No. 5,591,885. The process must be carried out at very low temperatures (T less than xe2x88x92xe2x88x9280xc2x0 C.) which limits the general industrial utility and incurs significant cost disadvantages.
The preparation of xcex1-chloroketones by reacting an N-protected amino ester with salts of chloroacetic acid and subsequent decarboxylation is disclosed, for example, by X. Wang et al., Synlett 2000, 902-904, and U.S. Pat. No. 5,929,284. For lithium salts, an industrial low temperature apparatus is again necessary. In the case of magnesium salts, the reaction may be carried out at or above room temperature, but the reaction then delivers only a 52% yield by chromatography.
The preparation of xcex1-chloroketones by reacting an activated N-protected amino acid with alkali metal enolates of acetates to give xcex2-ketoester derivatives which are then chlorinated selectively in the 2-position in a second step followed by decarboxylation in a third step is disclosed by EP 774 453 and U.S. Pat. Nos. 5,767,316 and 5,902,887. The three stage procedure is accordingly more costly and inconvenient than the previously described processes.
The preparation of xcex1-chloroketones by reacting an activated N-protected amino acid with alkali metal enolates of monohaloacetates to give halogenated xcex2-ketoester derivatives which are then hydrolyzed and decarboxylated in subsequent steps is described in U.S. Pat. Nos. 5,767,316 and 5,902,887. According to the inventors (EP 774 453 A1, page 5, lines 46-47), the process has to be carried out at xe2x88x9260xc2x0 C. or lower which again requires an industrial low temperature facility.
It is an object of the present invention to provide an inexpensive process for preparing an xcex1-haloketone from an N-protected amino acid derivative which may be carried out without risk on an industrial scale and which provides higher yields and purities than prior art processes. These and other objects are achieved by reacting a carboxylic acid derivative bearing a leaving group bonded to the carbonyl carbon, with a mono- or dienolate of a silyl ester.
Thus, the subject invention is directed to a process for preparing an xcex1-haloketone of the general formula (1) 
where R1 is an alkyl, aralkyl or aryl radical in which CH2 units may be replaced by heteroatoms such as NH, NCH3, S or O, and CH units may be replaced by N, and
the R1 radicals may further be substituted by functional groups, for example a halogen radical, an amino radical, an alkoxy radical or a thioalkyl radical and
R2 is a hydrogen, alkyl, aralkyl or aryl radical and
X is a halogen radical,
by reacting a carboxylic acid derivative of the general formula (2) 
where R1 is as defined above and
L is a leaving group,
with a mono- or dienolate of a silyl ester of the general formula (3) 
where X and R2 are each as defined above, and R3 and R4 are identical or different and are each hydrogen, alkyl, aryl, alkenyl or aralkyl;
and hydrolyzing the reaction product immediately after the reaction and preferably without isolation, by adding acid and decarboxylating to (1).
The leaving group L is preferably a radical which increases the reactivity of a carboxylic acid derivative toward nucleophiles compared to the free carboxylic acid and supports substitution by these nucleophiles at the carbonyl carbon of the carboxylic acid derivative.
R1 is preferably selected from the group of linear or branched alkyl radicals having from 1 to 25 carbon atoms, aryl radicals having from 6 to 30 carbon atoms and aralkyl radicals having from 7 to 31 carbon atoms, where the CH2 units of each radical may be substituted by heteroatoms such as NH, NCH3, S or O and the CH units by N, and the R1 radicals may optionally be substituted by non-interfering functional groups including halogen radicals, amino radicals, alkoxy radicals, and thioalkyl radicals. Examples of R1 include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, isopropyl, isobutyl, t-butyl, 2,2-dimethylpropyl, 3-methylbutyl, phenyl, naphthyl and benzyl radicals.
The leaving group L is preferably selected from among alkoxy radicals having from 1 to 10 carbon atoms, optionally ring-substituted phenoxy or benzyloxy radicals, halogen radicals such as bromine or chlorine radicals, imidazolyl radicals, 1-oxybenzotriazole, and alkoxycarbonyloxy groups such as methoxycarbonyloxy, ethoxycarbonyloxy and isobutoxycarbonyloxy (mixed anhydrides). The leaving group L is preferably a linear alkoxy radical having from 1 to 4 carbon atoms, and is more preferably the methoxy radical.
X is Cl, Br, F or I, more preferably Cl or Br, most preferably Cl.
Preferably, the R2 radicals are each independently hydrogen radicals, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 10 carbon atoms, aralkyl radicals having from 7 to 11 carbon atoms or alkenyl radicals having from 2 to 10 carbon atoms. A preferred R2 radical is the hydrogen radical.
The R3 and R4 radicals are preferably each independently hydrogen radicals, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 10 carbon atoms or alkenyl radicals having from 2 to 10 carbon atoms. Examples of SiR3R4 silyl radicals include the dimethylsilyl, diethylsilyl, diisopropylsilyl, di-(t-butyl)silyl, dibutylsilyl, t-butylmethylsilyl, phenylmethylsilyl, diphenylsilyl and divinylsilyl radicals. Preferred silyl radicals are dimethylsilyl and diphenylsilyl radicals. A particularly preferred silyl radical is the dimethylsilyl radical.
Preference is given to carrying out the inventive process at a temperature in the range from xe2x88x9210xc2x0 C. to 110xc2x0 C., more preferably from 0xc2x0 C. to 70xc2x0 C. The process requires only one process step, requires no low temperature facility and no dangerous chemicals, employs inexpensive silyl radicals, and delivers better yields than the prior art processes.
Preference is given to carrying out the process in the presence of a solvent. In addition to aromatic hydrocarbons such as benzene, toluene or xylene, and aliphatic solvents such as hexane or heptane, preferred solvents include ethers such as t-butyl methyl ether, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, and 1,2-dimethoxyethane.
It has surprisingly been discovered that silyl bis(xcex1-halocarboxylate) esters can form stable enolates at room temperature or even at elevated temperature with selected bases, and that these enolates add onto activated (amino) acid derivatives in the desired manner and give the desired xcex1-haloketones under acidic workup by immediate hydrolysis and in situ decarboxylation. In view of the prior art, it would have been expected that enolates of silyl haloacetates would only be suitable for preparing chloroketones at very low temperatures (T less than xe2x88x9260xc2x0 C.) and even then only in low yields of up to about 50%.
The present invention relates in particular to a process for preparing an xcex1-haloketone of the general formula (5) 
where R2 is as defined above and R5 is a hydrogen, alkyl, aralkyl or aryl radical in which one or more CH2 groups may be replaced by O, S, NH or NCH3, and
X is a halogen radical and
D1 and D2 are each independently a hydrogen radical or an amino protecting group, or are together a cyclic amino protecting group,
by reacting an amino acid derivative of the general formula (6) 
where R5, D1 and D2 are each as defined above and L is a leaving group as defined above, with a metal enolate of a silyl ester of the general formula (3) and hydrolyzing the reaction product immediately afterwards by adding acid and decarboxylating to (5).
Preference is given to selecting R5 from among hydrogen radicals, linear or branched alkyl radicals having from 1 to 20 carbon atoms where one or more CH2 groups may be replaced by O, S, NH or NCH3, aryl radicals having from 6 to 25 carbon atoms, aralkyl radicals having from 7 to 26 carbon atoms, optionally substituted vinyl and alkynyl radicals, and side chains of amino acids or of amino acid derivatives which are obtainable by chemical modification of the R1 side chain of a natural or non-natural amino acid.
Examples of R5 include hydrogen, methyl, ethyl, isopropyl, t-butyl, hydroxymethyl, chloromethyl, 1-hydroxyethyl, mercaptomethyl, methylthiomethyl, methylthioethyl, 2-methylpropyl, 1-methylpropyl, 1-hydroxyethyl, phenylthiomethyl, phenyl, benzyl, 2-phenylethyl, p-hydroxybenzyl, p-hydroxyphenyl, p-chlorophenyl, m-hydroxyphenyl, histidinyl, imidazolyl, triazolyl, tetrazolyl, 2-thiazolylthio, alkynyl, and vinyl radicals. Free hydroxyl, thiol or amino groups on the R5 radicals may also be provided, if desired, with a protecting group by methods known to those skilled in the art, for example as disclosed in P. J. Kocienski, PROTECTING GROUPS, Thieme Verlag, 1994, Stuttgart, New York, pages 185-243. R5 is more preferably a phenylthiomethyl or benzyl radical.
D1 and D2 are identical or different and are each preferably a hydrogen radical or amino protecting group. An amino protecting group is any protecting group which can be used for protecting amino functionality. Such protecting groups are well known Kocienski, id. Examples of such protecting groups include: methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (Z), fluorenyloxycarbonyl (FMOC), acetyl, benzyl, dibenzyl, phthalimido, tosyl, benzoyl, and silyl groups such as trimethylsilyl, stabase (2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane derivatives) and benzostabase (2,2,5,5-tetramethyl-1-aza-2,5-disilabenzocyclopentane derivatives). The protecting group is preferably a t-butoxycarbonyl (BOC) or a benzyloxycarbonyl (Z) group.
The carboxylic acid derivative (6) is preferably an optically active, enantiomerically pure L- or D-amino ester. The optically active, enantiomerically pure L- or D-amino ester is preferably a compound from the group of tert-butoxycarbonyl- or benzyloxycarbonyl-protected L-phenylalanine esters or L-S-phenylcysteine esters.
The metal enolates of the silanes (3) are generated by reacting the silanes with two or more molar equivalents of bases, preferably in ether solvent, for example tetrahydrofuran or methyl tert-butyl ether.
Suitable bases for generating the enolate, which deprotonate either only one or both optionally R2-substituted xcex1-halocarboxylic acid moieties include all strong bases such as the alkali metal bases or alkaline earth metal bases. Useful bases include organolithium compounds, for example n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, lithium cyclohexylamide, and lithium cyclopentylamide; potassium tert-butoxide, sodium compounds such as sodium hydride, sodium methoxide, sodium ethoxide and the analogous potassium compounds; magnesium amides such as diisopropylamidomagnesium chloride, diisopropylamidomagnesium bromide, hexamethyldisilazidomagnesium chloride, hexamethyldisilazidomagnesium bromide, magnesium bis(diisopropylamide), magnesium bis(hexamethyldisilazide), cyclohexylamidomagnesium chloride, and cyclohexylamidomagnesium bromide and organomagnesium compounds such as tert-butylmagnesium chloride, n-butylmagnesium chloride, methylmagnesium chloride, t-amylmagnesium chloride and the corresponding bromides of these compounds; di-tert-butylmagnesium and diisopropylmagnesium. When organometallic compounds are used, an amine such as diisopropylamine, hexamethyldisilazane, triethylamine or diisopropylethylamine may also be added before or during the reaction. The molar ratio between the organometallic compound and amine is from 0.1 to 10. Preferred bases are magnesium compounds.
Particularly preferred bases are magnesium amides or a combination of an alkylmagnesium compound with an amine. Preference is given to preparing these bases by reacting a magnesium amide of the general formula (8) 
where
R6 and R7 are each independently alkyl, aralkyl, aryl, or silyl radicals, or R6 and R7 together are a cycloalkyl ring having from 4 to 6 carbon atoms, and
Y is xe2x80x94NR6R7 or a halogen radical;
or by reacting an organomagnesium compound of the formula (9)
R8MgZxe2x80x83xe2x80x83(9)
where
R8 is an alkyl, aryl or aralkyl radical and
Z is a halogen radical or R3,
or mixtures of compounds (9) as present in particular in Grignard solutions known as the Schlenk equilibrium, with a silyl ester of the general formula (3).
For the purposes of the present invention, the metal enolate refers in general to the active species which forms in the reaction between the silyl ester (3) and a strong base, i.e. a metal cation, for example Li or Mg, in a suitable solvent.
The term magnesium enolate refers to the active species which forms in the reaction between the silyl ester (3) and a magnesium base such as diisopropylamidomagnesium chloride in a suitable solvent which may deprotonate either only one or both optionally substituted xcex1-halocarboxylic acid units.
Preferably, R6 and R7, independently, are linear or branched alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 10 carbon atoms, aralkyl radicals having from 7 to 15 carbon atoms or silyl radicals having from 3 to 10 carbon atoms. Examples of R6 and R7 radicals include the methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, benzyl and trimethylsilyl radicals, or R6 and R7 together may be xe2x80x94(CH2)4xe2x80x94or xe2x80x94(CH2)5xe2x80x94. Particular preference is given to compounds where R6 and R7 are the same, and are isopropyl or trimethylsilyl radicals.
R8 is preferably a linear or branched alkyl radical having from 1 to 10 carbon atoms, an aryl radical having from 6 to 10 carbon atoms or an aralkyl radical having from 7 to 15 carbon atoms. Examples of R8 include methyl, ethyl, propyl, isopropyl, t-butyl, iso-butyl, n-butyl, phenyl or benzyl radicals. R8 is more preferably a secondary or tertiary radical, for example an iso-propyl, sec-butyl or t-butyl radical.
Preference is given to carrying out the process of the invention in such a manner that a silyl ester (3) and a base of formula (8) or (9) and a carboxylic acid derivative of formula (2) or preferably an activated (amino) acid derivative of formula (6) are mixed together, preferably at from 0xc2x0 C. to room temperature in one of the abovementioned solvents, and the solution is either stirred at room temperature until complete conversion or heated for 10-180 min at 40-110xc2x0 C. On completion of the reaction, the solution which contains the addition product is admixed with dilute acid to liberate the product (1) or (5) in situ, and this mixture is extracted using a water-immiscible organic solvent, a haloketone-containing organic phase is removed, washed, preferably with a saturated NaHCO3 or NaCl solution, and dried, preferably over Na2SO4 or MgSO4. The solvent is then removed, the disiloxane formed is removed and the xcex1-haloketone is obtained as a crystalline residue.
The molar ratio of base to silyl ester is preferably from 1 to 8, more preferably from 2 to 6. The molar ratio of the silyl ester to the carboxylic acid derivative is preferably from 0.5 to 2, more preferably from 0.5 to 1.5.
The reaction time at room temperature is preferably from 1 h to 16 h or, when heated, from 10 min to 3 h. It is preferable to conduct the reaction at a temperature of from 40 to 110xc2x0 C., more preferably from 40 to 70xc2x0 C., owing to the increased rate of reaction. Room temperature is preferably a temperature of from 20 to 25xc2x0 C.
Reaction completion can be monitored by employing conventional techniques. When using diisopropylmagnesium chloride as base, completion may be recognized simply by clarification of the suspension to a solution. The workup procedure immediately following the actual reaction generally involves adding reaction batch slowly, for example dropwise, to dilute acid. In principle, only a pH in the range from acid to neutral is attained. Examples of usable acids include hydrochloric acid (i.e. from 2 to 30%) and sulfuric acid (i.e. from 2 to 20%) and the like, saturated ammonium chloride solution, or dilute acetic acid. On acidification, the product (1) or (5) is liberated in situ, since contact with water results in both the hydrolysis of the silyl ester immediately followed by decarboxylation to the haloketone.
After a neutral to acid pH of less than 7, preferably from 1 to 4, is attained and no more gas develops, the reaction mixture is extracted using a water-immiscible organic solvent. The water-immiscible organic solvent is preferably an acetic ester such as ethyl acetate, propyl acetate or butyl acetate, an ether such as t-butyl methyl ether, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether or 1,2-dimethoxyethane, or an aromatic hydrocarbon such as toluene, xylene or benzene. In principle, halogenated hydrocarbons such as dichloromethane or chloroform are also suitable, however, their higher densities may exacerbate problems associated with phase separation, requiring more extractant to be used. Following extraction, the haloketone-containing organic phase is preferably washed with saturated NaHCO3 and/or NaCl solution and preferably dried, for example, over Na2SO4 or MgSO4. After filtering off the drying agent and removing the solvent, the oligo- or polysiloxane formed is removed by stirring with petroleum ether.
The solid residue of xcex1-haloketone may be used directly or after recrystallization. Particularly useful solvents for recrystallization include alcohols such as ethanol, 2-propanol, 2-butanol, hexanol and 2-ethylhexanol. These may also be used as mixtures with petroleum ether. Recrystallization also removes the co-produced siloxane xe2x80x94[Si(CH3)2O]xe2x80x94, so that stirring with petroleum ether may be omitted.
The crude or recrystalized xcex1-haloketone may be reduced to form the corresponding xcex1-haloalcohol. Reduction to the xcex1-haloalcohol may take place by reduction of the xcex1-haloketone using NaBH4 under the conditions described by S. W. Kaldor et al., J. MED. CHEM. 1997, 40, 3979-3985, or, owing to the marked diastereoselectivity, most advantageously by Meerwein-Ponndorf-Verley (MPV) reduction as described, for example, in EP 963972, page 13, line 42 to page 14, line 11.
The following reaction scheme serves as a non-limiting example for the possible combinations of substrates and reagents of the present invention: 
The present invention therefore also encompasses the preparation of an xcex1-haloalcohol of the general formula (4) 
where R1, R2 and X are each as defined above by preparing an xcex1-haloketone (1) by the process according to the invention and reducing the carbonyl group to the xcex1-haloalcohol (4).
The invention also encompasses in particular the preparation of an xcex1-haloalcohol of the general formula (7) 
where R2, R5, D1, D2 and X are each as defined above,
by preparing an xcex1-haloketone (5) by the process according to the invention and reducing the carbonyl group to the xcex1-haloalcohol (7).
The process according to the invention allows advantageous, inexpensive access to xcex1-haloketones starting from (N-protected amino) acid derivatives. Starting from L-phenylalanine and L-phenylcysteine, reduction of the keto group gives the corresponding haloalcohols which can be further reacted to give HIV protease inhibitors (S. W. Kaldor et al., J. Med. Chem. 1997, 40, 3979-3985; K.-J. Schleifer, Pharmazie in unserer Zeit 2000, 29, 341-349).
In addition, purification may be effected by simple recrystallization. Column chromatography, which cannot be carried out on an industrial scale, is unnecessary.
The following examples serve to illustrate the invention: